Dosing regimens for several drugs used in treating renal diseases, most notably the aminoglycosides, are based upon a measurement of renal function known as the glomerular filtration rate (GFR). It is often necessary to estimate GFR, since actual measurement is both expensive and time-consuming. However, standard methods for estimating renal function are prone to errors which can result in inaccurate drug dosages being prescribed to an individual. These inaccuracies have created substantial risk of nephrotoxicity in underweight patients and insufficient dosages being prescribed to overweight or obese subjects.
The reported incidence of aminoglycoside nephrotoxicity ranges from 0-50%, with rates in most studies in the 5-25% range. Prospective studies that defined nephrotoxicity as a substantial decrease in the GFR reported an incidence of nephrotoxicity that ranged from 5-10% in severely ill patients. Aminoglycoside toxicity can be minimized if such drugs are dosed appropriately.
In clinical practice, renal function can be estimated through measurement of inulin clearance (CL.sub.IN) or creatinine clearance (CL.sub.CR). Measurement of CL.sub.IN is preferred by many clinicians because inulin is an inert sugar that is cleared solely by glomerular filtration. Because inulin is neither secreted nor absorbed by the renal tubules, it is believed to be a relatively accurate indicator of GFR.
However, measurements of CL.sub.IN can vary by as much as 20% in an individual at a given time. In addition, determination of CL.sub.IN is not practical in an everyday clinical setting. The procedure requires intravenous infusion of inulin followed by three timed urine collections. Thus, measurement of CL.sub.IN is laborious, time-consuming and expensive.
Measurement of CL.sub.CR is a practical substitute for CL.sub.IN in estimating renal function. Creatinine, which is a product of muscle metabolism, is eliminated by the kidneys mainly by glomerular filtration, but also to a minor extent by tubular secretion. For this reason, CL.sub.CR measurements usually overestimate the GFR in comparison to CL.sub.IN. However, CL.sub.CR measurement is simpler and less expensive to perform.
There are several methods for estimating CL.sub.CR. The standard method involves collecting the urine output (V.sub.U) from a subject for a 24-hour period and measuring urine (U.sub.CR) and serum (S.sub.CR) creatinine concentrations. Creatinine clearance is then calculated as: EQU CL.sub.CR =(U.sub.CR) (V.sub.U)/(S.sub.CR)
Some studies suggest that shorter collection periods (i.e. 30 minutes to two hours) are as predictive of GFR as the 24-hour collection period. However, many patients who are admitted to a hospital require urgent administration of aminoglycosides or other potentially toxic medications in a time frame that does not allow for such measurements of CL.sub.CR.
Because of this, a number of authors have developed mathematical equations to estimate GFR. The equation that is most commonly used in clinical practice is the Cockcroft-Gault (C-G) equation. There are different forms of the C-G equation that use either ideal body weight or actual body weight. The C-G equation using ideal body weight for male subjects is expressed as: EQU Estimated Male CL.sub.CR =(140-age).times.IBW/(72.times.S.sub.CR) !
where IBW and age refer to a patient's ideal body weight (kg) and physical age, respectively. For female subjects, the corresponding C-G equation is: EQU Estimated Female CL.sub.CR =(0.85.times.Estimated male CL.sub.CR).
In turn, ideal body weight is calculated as: EQU Male IBW (kg)=50+2.3.times.(Height in inches-60)! EQU Female IBW (kg)=45+2.3.times.(Height in inches-60)!
The above C-G equations assume that a subject is in a steady-state, that skeletal mass is a constant percentage of weight and that deviations from ideal weight do not affect renal function. However these assumptions may not be true, particularly in cases where a patient is malnourished or severely ill, thereby diminishing the accuracy of renal function determination using the C-G equations. It has been determined, in fact, that the C-G equations are prone to error, especially where a subject's body weight varies from his or her IBW.
Moreover, individual variables in the equation such as age, S.sub.CR, IBW, height and sex do not correlate with measured CL.sub.CR. Actual body weight as a percent of ideal, however, correlated with CL.sub.CR, suggests that the C-G equations systematically overestimate CL.sub.CR in subjects below IBW and underestimate CL.sub.CR in subjects over IBW. A physician relying on these equations would, thus, over-prescribe medication for underweight subjects and under-prescribe medications in overweight patients.
Substitution of actual weight for IBW in the C-G equation somewhat improved the prediction of CL.sub.CR. Still, published case series have reported an incidence of aminoglycoside nephrotoxicity ranging from 0 to 25% based upon use of the C-G equations. In light of this, several other authors have made attempts at improving predictive formulae.
Boyce et al. concluded that the C-G equation used with the lower of either ideal or actual weights was the most precise and least biased method for testing malnourished patients. E. G. Boyce et al., Creatinine Clearance Estimation in Protein-Malnourished Patients, 8 Clin. Pharm. 721, 726 (1989).
M. Smythe et al. concluded that in elderly patients with low S.sub.CR, correcting serum creatinine in the C-G equations to 1.0 mg/dL led to underestimates of both CL.sub.CR and the dosages of aminoglycosides. M. Smythe et al., Estimating Creatinine Clearance in Elderly Patients with Low Serum Creatinine Concentrations, 51 Am. J. Hosp. Pharm. 198, 204 (1994).
O'Connell et al. found the Jelliffe 1973 equation using modified lean body weight was best for predicting the correct drug doses for hospitalized elderly patients. M. B. O'Connell et al., Predictive Performance of Equations to Estimate Creatinine Clearance in Hospitalized Elderly Patients, 26 Ann. Pharmacother. 627, 635 (1992).
Bertino concluded that in patients with an S.sub.CR Of less than 1.0 mg/dL, the actual S.sub.CR level should be used when calculating CL.sub.CR by the C-G equations. J. S. Bertino, Jr., Measured Versus Estimated Creatinine Clearance in Patients with Low Serum Creatinine Values, 27 Ann. Pharmacother. 1439, 1441 (1993).
Only two studies of renal function are known to have used bioimpedance analysis (BIA) to predict CL.sub.CR. In the first, reported by A. S. Smythe et al., Relationship Between Values of Bioelectrical Impedance and Creatinine Clearance, 10 Pharmacotherapy 42, 46 (1990), BIA was performed on 28 healthy adult volunteers. They measured CL.sub.CR using 24-hour urine collection and calculated CL.sub.CR using seven predictive formulae.
Multiple linear regression analysis of the findings of Smythe et al. revealed that measured S.sub.CR and resistance (R), determined by BIA were significant predictors of measured CL.sub.CR. The authors derived a predictive equation: EQU CL.sub.CR =288.3-0.202(R)-66.64(S.sub.CR)
The mean absolute prediction error for CL.sub.CR determined by this method was significantly lower than those obtained from 4 of 7 standard CL.sub.CR predictive equations.
In the second study, S. Robert et al., Predictability of Creatinine Clearance Estimates in Critically Ill Patients, 21 Crit. Care Med. 1487, 1495 (1993), CL.sub.IN was used as the criterion method for GFR, from which CL.sub.CR was calculated using 30-minute and 24-hour urine collection techniques. The authors utilized BIA to measure lean body mass (LBM) and then used LBM in place of weight in the C-G equation to predict CL.sub.CR with a corrected S.sub.CR.
In this latter study, LBM and a corrected S.sub.CR tended to overestimate the GFR. The research concluded that equations using the lower of IBW or actual body weight along with a corrected S.sub.CR were significantly better predictors of CL.sub.IN than either the 30-minute or 24-hour urine collection techniques. However, the results of Robert et al. indicate a greater than 20% disparity between the modified C-G equations and CL.sub.IN in 55% of their subjects.
With the inconclusive and varied results above, the issues of how to best express weight in the calculation and whether or not to correct S.sub.CR in the C-G equations remain unresolved. Furthermore, no equations have yet been determined which can apply to all groups of patients, regardless of such factors as age, race, gender, nutritional status, or those affected by disease. Improving the prediction of CL.sub.CR could decrease the incidence of nephrotoxicity independent of dosing frequency, which could in turn lead to cost savings in medical care.